Of the 1 million cases of newly diagnosed breast cancer worldwide each year, over 170,000 cases are a distinct type of triple-negative breast cancer (TNBC). TNBC lacks expression of estrogen (ER), progesterone (PR) and Her-2/neu. It is not a candidate for two common therapies for breast cancer: hormonal (tamoxifen) and Her-2 targeted (Herceptin) therapy. TNBC is usually found at the late stage and has a higher likelihood of local and distant recurrence and a poor prognosis. The goal of this study is to develop a complete therapeutic approach that merges targeted preoperative adjuvant therapy and image-guided treatment and surgery for preventing local recurrence and distant metastasis. Our team has developed a multifunctional nanoparticle platform that carries therapeutic agents, targets tumor cells and stromal tissues, and produces optical and MR imaging signals. We demonstrated the ability of targeted tumor imaging, tumor growth inhibition, and anti- angiogenesis effects in TNBC animal models. In the proposed study, we will develop receptor-targeted and near infrared dye labeled-magnetic iron oxide nanoparticles (IONPs). These nanoparticles will carry DNA damaging drugs without or with a poly ADP ribose polymerase (PARP) inhibitor for treatment of TNBC, MRI monitoring of drug delivery and response, and optical image-guided surgery. We hypothesize that targeted delivery of high concentrations of the combined therapeutic agents using theranostic nanoparticles and timely assessment of drug delivery and response to the treatment could lead to enhanced therapeutic effects in drug resistant tumor cells, while minimizing systemic toxicity. Image-guided surgery following the targeted therapy allows removal of small drug-resistant residual tumor lesions, which could prevent the development of local recurrence and distant metastasis. First, urokinase plasminogen activator receptor (uPAR) and epidermal growth factor receptor (EGFR) will be validated as molecular targets for targeted therapeutics using two large cohorts (>3000 cases) of breast cancer tissues (Aim 1). We will produce a new generation of theranostic nanoparticles with enhanced drug delivery into the tumor by avoiding macrophage uptake and increasing in drug loading and release. We will determine biodistribution, and the effects of targeted therapy, MRI-guided drug delivery and evaluating response in TNBC animal models using different theranostic IONPs to select the lead theranostic IONPs for further preclinical studies (Aim 2). We will use the mice bearing orthotopic TNBC to study the effects of integration of preoperative targeted neoadjuvant therapy, monitoring therapeutic responses by non-invasive MRI, and intraoperative optical imaging of tumor lesions after administration of the theranostic IONPs on the incidences of local and distant recurrence as well as overall survival of the mice (Aim 3). We will examine systemic toxicity, and pharmacokinetics/pharmacodynamics of the selected lead theranostic IONPs in normal and tumor bearing mice (Aim 4). Clinical impact: The proposed study addresses the urgent need in clinical management of TNBC to improve the survival of patients afflicted with TNBC.